IGF1R is a transmembrane RTK that binds primarily to IGF-1 but also to IGF-II and insulin with lower affinity. Binding of IGF-1 to its receptor results in receptor oligomerization, activation of tyrosine kinase, intermolecular receptor autophosphorylation and phosphorylation of cellular substrates (major substrates are IRS1 and Shc). The ligand-activated IGF1R induces mitogenic activity in normal cells and plays an important role in abnormal growth. A major physiological role of the IGF-1 system is the promotion of normal growth and regeneration. Overexpressed IGF1R (type 1 insulin-like growth factor receptor) can initiate mitogenesis and promote ligand-dependent neoplastic transformation. Furthermore, IGF1R plays an important role in the establishment and maintenance of the malignant phenotype. Unlike the epidermal growth factor (EGF) receptor, no mutant oncogenic forms of the IGF1R have been identified. However, several oncogenes have been demonstrated to affect IGF-1 and IGF1R expression. The correlation between a reduction of IGF1R expression and resistance to transformation has been seen. Exposure of cells to the mRNA antisense to IGF1R RNA prevents soft agar growth of several human tumor cell lines. IGF1R abrogates progression into apoptosis, both in vivo and in vitro. It has also been shown that a decrease in the level of IGF1R below wild-type levels causes apoptosis of tumor cells in vivo. The ability of IGF1R disruption to cause apoptosis appears to be diminished in normal, non-tumorigenic cells.
The IGF-1 pathway in human tumor development has an important role. IGF1R overexpression is frequently found in various tumors (breast, colon, lung, sarcoma) and is often associated with an aggressive phenotype. High circulating IGF1 concentrations are strongly correlated with prostate, lung and breast cancer risk. Furthermore, IGF1R is required for establishment and maintenance of the transformed phenotype in vitro and in vivo (Baserga R. Exp. Cell. Res., 1999, 253, 1-6). The kinase activity of IGF1R is essential for the transforming activity of several oncogenes: EGFR, PDGFR, SV40 T antigen, activated Ras, Raf, and v-Src. The expression of IGF1R in normal fibroblasts induces neoplastic phenotypes, which can then form tumors in vivo. IGF1R expression plays an important role in anchorage-independent growth. IGF1R has also been shown to protect cells from chemotherapy-, radiation-, and cytokine-induced apoptosis. Conversely, inhibition of endogenous IGF1R by dominant negative IGF1R, triple helix formation or antisense expression vector has been shown to repress transforming activity in vitro and tumor growth in animal models.
It has been shown that mammalian target of rapamycin (mTOR) inhibition can induce upstream insulin-like growth factor 1 receptor (IGF1R) signaling resulting in AKT activation in cancer cells. This phenomenon has been suggested to play a role in the attenuation of cellular responses to mTOR inhibition and may attenuate the clinical activity of mTOR inhibitors. Increase in pAKT has for instance been found in approximately 50% in the tumours of all patients in a Phase I study in patients with advanced solid tumours (Taberno et al., Journal of Clinical Oncology, 26 (2008), pp 1603-1610).